This is a systematic long-term program to develop mild chemical methods for peptide synthesis. The theoretical basis of these studies is the concept of orthogonal protection, and the experimental cornerstone is the new N-alpha-dithiasuccinoyl (Dts) amino protecting group, which can be rapidly and quantitatively removed under neutral conditions by reduction with thiols. A complete set of orthogonally protected N-alpha-Dts amino acid derivatives shall be prepared and applied to the synthesis of biologically active peptides. As a culmination of this line of research, the first total synthesis of an iron-sulfur protein, namely crystalline ferredoxin (55 residues) shall be attempted. Amino acid replacement analogues of this protein are contemplated which may shed light on the molecular details of electron transport. The principles of orthogonal solid-phase peptide synthesis shall be further elaborated by the development of new anchoring linkages and new thiolysable side-chain protecting groups. These methods will facilitate the preparation of fragile and structurally complex biomolecules. The mild and specific chemistry of thiolysis of dithiasuccinoyl-amines will be exploited in a series of biochemically oriented studies. These will have consequences for intracellular drug delivery, for the design of affinity labels based on biologically significant amines, and for the directed synthesis of asymmetrical disulfides.